Journal
CELL REPORTS
Volume 22, Issue 13, Pages 3612-3624Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2018.03.021
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Funding
- Alborada Trust (ARUK Stem Cell Research Centre)
- Dementias Platform UK [RG86395]
- Wellcome Trust [203144, RG69895]
- Cancer Research UK [C6946/A24843]
- AstraZeneca
- Talisman Therapeutics
- MRC [MR/L023784/2, MR/L023784/1] Funding Source: UKRI
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In Alzheimer's disease, neurofibrillary tangle pathology appears to spread along neuronal connections, proposed to be mediated by the release and uptake of abnormal, disease-specific forms of microtubule-binding protein tau MAPT. It is currently unclear whether transfer of tau between neurons is a toxic gain-of-function process in dementia or reflects a constitutive biological process. We report two entry mechanisms for monomeric tau to human neurons: a rapid dynamin-dependent phase typical of endocytosis and a second, slower actin-dependent phase of macropinocytosis. Aggregated tau entry is independent of actin polymerization and largely dynamin dependent, consistent with endocytosis and distinct from macropinocytosis, the major route for aggregated tau entry reported for non-neuronal cells. Anti-tau antibodies abrogate monomeric tau entry into neurons, but less efficiently in the case of aggregated tau, where internalized tau carries antibody with it into neurons. These data suggest that tau entry to human neurons is a physiological process and not a disease-specific phenomenon.
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